Showing papers by "Joseph L. Izzo published in 2005"

Expanding the definition and classification of hypertension.

Abstract: Cardiovascular abnormalities are frequently the cause, as well as the effect, of elevated blood pressure. As such, early cardiovascular disease (CVD) may be established before identifiable blood pressure thresholds are crossed. To identify individuals at risk for CVD at an earlier point in the disease process, as well as to avoid labeling persons as hypertensive who are at low risk for CVD, the Hypertension Writing Group proposes incorporating the presence or absence of cardiovascular risk factors, early disease markers, and target organ damage into the definition and classification scheme of hypertension. To describe both the complexity and progressive nature of hypertension, the following definition is proposed: "Hypertension is a progressive cardiovascular syndrome arising from complex and interrelated etiologies. Early markers of the syndrome are often present before blood pressure elevation is observed; therefore, hypertension cannot be classified solely by discrete blood pressure thresholds. Progression is strongly associated with functional and structural cardiac and vascular abnormalities that damage the heart, kidneys, brain, vasculature, and other organs and lead to premature morbidity and death." Classification of hypertension must involve assessing global cardiovascular risk to situate an individual's risk for CVD and events along a continuum. As knowledge of early CVD continues to evolve, the approach to classifying individuals along that continuum can be expected to evolve accordingly. The four categories currently used to classify hypertension are normal, prehypertension, and stages 1 and 2 hypertension. The population identified with prehypertension includes a subgroup with early CVD. We believe it would be preferable to classify all individuals as either normal or hypertensive, based on their cardiovascular evaluation, using the four categories of normal and stages 1, 2, and 3 hypertension.

Changes in Aortic Stiffness and Augmentation Index After Acute Converting Enzyme or Vasopeptidase Inhibition

Abstract: Augmentation index (AI), a measure of enhanced wave reflection, has been proposed as a bedside measure of aortic stiffness. However, because AI is potentially sensitive to various factors other than vessel wall stiffness, the utility of AI as a stiffness indicator may be limited. To assess relations between AI and vascular properties, we used arterial tonometry and aortic Doppler flow to evaluate trough (24 hours) and peak (4 hours) pulsatile hemodynamics and pulse wave velocity in 159 individuals with systolic hypertension at the completion of a 12-week period of monotherapy with the vasopeptidase inhibitor omapatrilat (80 mg; n=75) or the converting enzyme inhibitor enalapril (40 mg; n=84). Characteristic impedance (Zc) was calculated from the ratio of change in carotid pressure and aortic flow in early systole. Systolic ejection period (SEP), timing of wave reflection, and AI were assessed from the carotid waveform. Comparable acute reductions in mean pressure were associated with greater reductions in peripheral resistance with enalapril, whereas neither drug had an acute effect on Zc. Both drugs reduced AI, but neither drug altered the timing of wave reflection. Both drugs increased heart rate and shortened SEP. Multiple regression analysis demonstrated that the acute reduction in AI was most affected by reductions in SEP and peripheral resistance. Change in AI was inversely related to change in Zc and pulse wave velocity did not enter the model. Our findings indicate that AI is a complex surrogate marker that is inversely related to changes in proximal aortic stiffness in systolic hypertension.

Aging, Arterial Stiffness, and Systolic Hypertension

Abstract: Within the past few years, the paradigm in hypertension has shifted from an emphasis on diastolic blood pressure (DBP) to one that emphasizes the importance of systolic blood pressure (SBP), especially in individuals over age 50 years (1, 2, 3, 4). The rationale for this shift is based on a large body of observational and clinical trial data demonstrating that SBP is a better risk predictor, and that SBP control markedly reduces cardiovascular morbidity and mortality. At the same time, there has been relatively little information available to practitioners about the many new concepts that underlie this new approach to cardiovascular patho-physiology. Most important is the notion that age-related changes in vascular stiffness are at the center of future efforts to provide important new diagnostic and therapeutic advances in hypertension care.

Mechanisms of Angiotensin II–Mediated Decreases in Intraneuronal Ca2+ in Calcium-Loaded Stellate Ganglion Neurons

Abstract: Our laboratory has reported previously that angiotensin II, type-1 (AT(1)) receptor stimulation in isolated stellate ganglion neurons decreases intraneuronal calcium concentration ([Ca(2+)]i) acutely if baseline [Ca(2+)]i is high and increases [Ca(2+)]i if baseline [Ca(2+)]i is low. Part of the angiotensin II (Ang II) effect in high Ca(2+) neurons is mediated through stimulation of Na(+)-Ca(2+) exchange. Current experiments were conducted to identify additional steps in the signaling pathways. In Ca(2+)-loaded neurons, Ang II-induced decreases in [Ca(2+)]i were attenuated by phospholipase C inhibition (U73122) or nitric oxide (NO) synthase inhibition (L-NMMA) and were mimicked by the cGMP analogue 8-Br-cGMP. Protein kinase C (PKC) inhibition (bisindolylmaleimide I or Go6976) and protein kinase G (PKG) inhibition (KT5823) partially blocked Ang II-mediated decreases in [Ca(2+)]i, but complete blockade of Ang II effects was obtained with combined PKC and PKG inhibition. Modulation of inositol triphosphate (IP(3))-inducible ER Ca(2+) release by [Ca(2+)]i was investigated using furaptra, an ER-retaining dye. IP(3)-mediated ER Ca(2+) release in beta-escin-permeabilized neurons was measured after clamping of [Ca(2+)]i from 50 nM to 800 nM. Maximal ER Ca(2+) release was observed at approximately 200 nM [Ca(2+)]i, with noted blunting of release at higher [Ca(2+)]i. Steady-state mRNA transcript and protein levels revealed that the principal IP(3)R isoform expressed was IP(3)R-II. These results suggest that Ca(2+) loading in stellate ganglion neurons promotes Ang II-mediated decreases in [Ca(2+)]i via PKC and NO/cGMP/PKG pathways and inhibits IP(3)R-II-mediated ER Ca(2+) release.

Your Drug, My Drug, or Our Drugs: How Aggressive Should We Be With Antihypertensive Therapy?

Abstract: In the prevention of hypertensive complications, especially stroke and kidney disease, “lower is better” because for each decrease of 20 mm Hg systolic or 10 mm Hg diastolic pressure in the population, cardiovascular risk is halved. Ideally, the goal for each patient should be to reach the lowest blood pressure that is well tolerated, a value that may be well below the arbitrary threshold value of 140/90 mm Hg. For the majority of “uncomplicated hypertensives,” the question of single-drug therapy is essentially moot, because more than one agent is almost always required to optimally control blood pressure. In individuals who already have heart or kidney disease, there are compelling indications for the use of drugs that block the renin-angiotensin system, but the large outcome studies that spawned these recommendations are themselves combination trials. Thus, in virtually all patients, more than one drug is indicated. The best combinations take advantage of long durations of action and complementary mechanisms of action of the component and are not only able to effectively lower blood pressure, but also to favorably affect the natural history of hypertensive complications. Regimens—including fixed-dose combination products—that combine a thiazide diuretic or calcium antagonist with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker are most efficient. In summary, why would an astute clinician (or informed patient) be satisfied with the relatively limited effects of any single class of antihypertensive agents when better overall protection is possible?